A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network. Issue 22 (6th September 2016)

• Record Type: Journal Article
• Authors: Unnikrishnan, Ashwin; Guan, Yi F.; Huang, Yizhou; Beck, Dominik; Thoms, Julie A. I.; Peirs, Sofie; Knezevic, Kathy; Ma, Shiyong; de Walle, Inge V.; de Jong, Ineke; Ali, Zara; Zhong, Ling; Raftery, Mark J.; Taghon, Tom; Larsson, Jonas; MacKenzie, Karen L.; Van Vlierberghe, Pieter; Wong, Jason W. H.; Pimanda, John E.
• Is Part Of: Nucleic acids research. Volume 44:Issue 22(2016)
• Page Start: 10644
• Page End: 10661
• Publication Date: 2016-09-06
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkw804
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The E TS-r elated g ene ( ERG ), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34 + haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.